Inflammation is a host response to infection and injury. Inflammatory cells respond to foreign substances and inflammatory stimuli by producing bioactive mediators such as prostanoids, cytokines and chemokines that interact with many cell types to amplify the inflammatory response (Krakauer, 2004, Curr. Drug Targets-Inflammation and allergy 3(3): 317-324). Deregulation of these processes leads to acute and chronic inflammatory diseases for which pharmacological intervention is necessary to attenuate cellular inflammation pathways.
Chronic inflammation and infections lead to the up-regulation of pro-inflammatory enzymes like iNOS and COX2, which are responsible for elevated levels of NO (nitric oxide) and prostaglandins (PGs), respectively. Aberrant production or overproduction of NO has been implicated in the pathogenesis of cancer via reactive nitrogen oxide species-mediated reactions (Heiss et al., 2001, J Biol Chem 276(34): 32008-32015; Sporn and Roberts, 1986, J Clin Invest 78:329-332). PGs have a role as pro-inflammatory mediators.
The pro-inflammatory enzymes are involved in the pathogenesis of many chronic diseases including multiple sclerosis (MS), Parkinson's disease, Alzheimer's disease, and colon cancer (Oshima et al., 1996, Mutat. Res. 305:253-264; Takahashi et al., 1997, Cancer Res 57:1233-1237; Hooper et al., 1997, Proc Natl Acad Sci USA 94: 2328-2333; Simonian and Coyle, 1997, Annu Rev Pharmacol Toxicol 36: 83-106; Hantraye et al., 1996, Nat Med 2: 1017-1021). iNOS plays an important role in the inflammatory response of tissues to injury and infectious agents. Chronic inflammation, carcinogenesis, and metabolic syndrome are thought to be mechanistically linked (Ohshima and Bartsch 1994, Mutat. Res 305: 253-264; Esposito and Giugliano 2004).
PEITC, an organo-sulfur bio-active compound, has many well-documented cancer chemo-preventive properties, the most significant one being the anti-carcinogenic effects to tobacco smoke. Its anti-cancer activities have been demonstrated in humans as well as in different animal models (Stoewsand, 1995, Food Chem Toxicol 33:537-43; Heiss et al., 2001, J Biol Chem 276:32008-32015; Chen et al., 2003, Planta Med 69:696-700; Gerhauser et al., 2003, Mutat Res 523-524:163-172, Rose et al. 2005, Nitric Oxide 12:237-243.)
Pro-inflammatory cytokines like interleukin-1-β (IL1β) are mediators in the pathogenesis of many chronic inflammatory diseases including rheumatoid arthritis (RA), a classic example of autoimmune disorder (Martin et al., 1995, J. Neuroimmunol 61:241). It plays a significant role in destructive processes, in synovitis and cartilage destruction. Chronic inflammation may represent a triggering factor in the origin of metabolic syndrome: stimuli such as over-nutrition, physical inactivity and aging would result in cytokine (like IL1β) hypersecretion and eventually lead to insulin resistance and diabetes in genetically or metabolically predisposed individuals (Esposito and Giugliano 2004). The occurrence of metabolic syndrome is highly prognostic of future risk of cardiovascular events.
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed and used drugs for rheumatologic as well as non-rheumatologic conditions (Brooks 1998; Clements and Paulus, 1981, in Textbook of Rheumatology 4th Ed; 700-730). More than 1% of the U.S. population uses these drugs on a daily basis. Worldwide, more than 30 million people consume NSAIDs daily (Baum et al., 1985, Arthritis Rheum 28: 686-692).
Characterization and use of effective anti-inflammatory agents are important issues for public health. Almost every known NSAID has moderate to severe side-effects of various kinds. NSAIDs such as Aspirin inhibit the activity of both constitutive COX1 and inducible COX2. Consequently they can cause platelet dysfunction, gastrointestinal ulceration and renal damage, since COX1 helps to maintain normal physiological functions such as mucus production in the gastric mucosa (Pathak et al., 2005, Eur J Cancer 41(1):61-70). For this reason, selective COX2 inhibitors, such as celecoxib and rofecoxib had been more attractive as anti-inflammatory as well as potential chemopreventive agents, although their potential toxicities were never disregarded (Bombardier et al., 2000, N Engl J Med 343(21):1520-1528). Mounting evidence suggests a cardio-protective effect of COX2 and potential detrimental effects of COX2 inhibitors on the heart (Wu et al., 2003, Am J Physiol Heart Circ Physiol 285(6):H2420-2429). The safety issue of drugs containing COX2 inhibitors has become a matter of widespread controversy (Juni et al., 2005, BMJ 330: 1342-1343).
The serious ramifications from inflammation and inflammation-related diseases are clear. Yet, drugs in use to treat these conditions have secondary harmful or potentially harmful effects. What is needed is new therapeutic products that exert anti-inflammatory effect through different metabolic pathways than the present drugs, thus avoiding the known negative side effects.